The etiology of adolescent idiopathic scoliosis (AIS), a disease affecting 0.2 to 6% of the population, is unclear. AIS affects mainly girls in number and severity but in spite of several studies suggesting a genetic predisposition, the form of inheritance remains uncertain (3;4;4-6). Several divergent perspectives have been postulated to better define this etiology (reviewed in (2;21-23)). Genetics, growth hormone secretion, connective tissue structure, muscle structure, vestibular dysfunction, melatonin secretion, and platelet microstructure are major areas of focus. The current opinion is that there is a defect of central control or processing by the central nervous system (CNS) that affects a growing spine and that the spine's susceptibility to deformation varies from one individual to another.
CNS Hypothesis: B. Muscle Spindle Ontology and AIS
In 1999, Dubousset suggested that AIS is probably caused by a proprioception control problem, a neuromuscular disorder in relation with the neurotransmitter involved with the bipedal condition.
Muscles spindles are skeletal muscle sensory organs that provide axial and limb position information (proprioception) to the CNS. It has been proposed that muscle spindles act as muscle receptors involved in the detection of movement, both passive and active.(5) Spindles consist of encapsulated muscles fibers (intrafusal fibers) that are innervated by specialized motor and sensory axons. Indeed, histologic and histochemical analysis of the distribution of muscle spindles in paraspinal musculature of patients suffering from AIS show few muscle spindles in the scoliotic muscle.(6) Although the mechanism involved in spindle ontogeny are poorly understood, the innervation of a subset of developing myotube (type I) by peripheral sensory afferents (group Ia) is a critical event for inducing intrafusal fiber differentiation and subsequent spindle formation. The inactivation of Egr3, a zinc-finger transcription factor, by gene targeting generates mice exhibiting gait ataxia, increased frequency of perinatal mortality, scoliosis, resting tremors and ptosis. Egr3-deficient mice lacked muscles spindles, a finding that is consistent with their profound gait ataxia. Egr3 is highly expressed in developing muscle spindles, but not in Ia afferent neurons or their terminals during developmental periods that coincide with the induction of spindle morphogenesis by sensory afferent axons. This indicates that type I myotubes are dependent upon Egr3-mediated transcription for proper spindle development.(7-9) In addition, Rodgers et al., reported the detection of Pax7 expression, a member of the Pax family of transcription factor, in the capsules surrounding adult mouse muscle spindles where it may be implicated in the formation and maintenance of neuromuscular contacts within the muscle spindles throughout life.(10) The recent report of Ichikawa et al.,(11) showing in muscle spindles the presence of OPN-immunoreactive spiral axon terminals suggest that OPN could behave as a molecular mechanoreceptor within the spindles. This aspect is further supported from the fact that OPN-null mice, which are normal and viable, are not responding to biomechanical stimuli.
Neuroendocrine Hypothesis
Recent experiments involving pinealectomy in chicken and more recently in rats maintained in a bipedal mode led to an alternate hypothesis. These surgeries produced a scoliosis (7;8;8-10) resembling in many aspects the human disease and pointed to a neuroendocrine hypothesis involving a melatonin deficiency as the source for AIS. Treatment after pinealectomy in both animal models with melatonin, the major hormone of the pineal gland, prevented the formation of scoliosis (11).
The biological relevance of melatonin in AIS remains controversial however since no significant decrease in circulating melatonin level has been observed in a majority of studies (12;13;13;14).
There is therefore a need for a useful method for diagnosing AIS and other diseases involving spinal deformities and for identifying compounds for treating these diseases.